Partners Ionis Pharmaceuticals and AstraZeneca (AZ) have announced that the Phase III CARDIO-TTRansform trial of Wainua (eplontersen), an antisense oligonucleotide (ASO) for transthyretin amyloid cardiomyopathy (ATTR-CM), failed to meet its primary composite endpoint of cardiovascular death and recurrent cardiovascular events at week 140. The setback, attributed partly to the high background use of TTR stabilisers (such as tafamidis and acoramidis) in the trial – which may have obscured incremental benefit – sent Ionis shares down 24%. Separately, Roche announced termination of two Huntington's disease programmes (tominersen and RG6496) originated by Ionis.

The trial highlights the challenge of demonstrating added value atop evolving standard-of-care regimens in long-duration cardiovascular studies. A prespecified single-agent subgroup suggested a nominal hazard ratio of 0.71, but this did not overcome the overall negative result.

Eplontersen remains approved for ATTR polyneuropathy (ATTRv-PN); however, the ATTR-CM indication is now in question pending fuller data analysis. The outcome contrasts with Alnylam's vutrisiran, which met its primary endpoint in HELIOS-B.